What is the differential diagnosis for a patient with low alkaline phosphatase?

Differential Diagnosis of Low Alkaline Phosphatase

In a patient with persistently low alkaline phosphatase (ALP < 40 IU/L), hypophosphatasia is the most common genetic cause and must be systematically distinguished from secondary causes including malnutrition, micronutrient deficiencies, endocrine disorders, antiresorptive medications, and Wilson disease in the setting of acute liver failure. 1, 2

Primary Genetic Cause

Hypophosphatasia is the leading genetic disorder causing low ALP, resulting from loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase. 1, 2

Clinical Manifestations

• Adults typically present with musculoskeletal pain, skeletal pain, chondrocalcinosis, calcific periarthritis, stress fractures, and pseudofractures 1, 2
• Premature loss of primary teeth (often before the usual eruption age) is a characteristic feature 1
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation 3
• In osteoporosis clinic patients with low ALP, hypophosphatasia is diagnosed in approximately 3% 4

Biochemical Markers

• Elevated pyridoxal-5'-phosphate (PLP, vitamin B6) is a key diagnostic marker; approximately 24% of individuals with low ALP have PLP levels above the reference range, and all of these carry an ALPL mutation 3
• Elevated urinary phosphoethanolamine (PEA) supports the diagnosis 2, 3
• ALP levels inversely correlate with serum calcium (r=-0.38), PLP (r=-0.51), and urinary PEA (r=-0.49) 3
• Bone-specific ALP may be low even when total ALP is normal, highlighting the importance of measuring bone-specific ALP when hypophosphatasia is suspected 5

Diagnostic Thresholds

• Persistent low ALP in adults is defined as serum concentration < 40 IU/L 1
• Some osteoporosis guideline societies use a stricter cutoff of < 30 IU/L when screening for hypophosphatasia 1, 4

Wilson Disease (Critical to Recognize)

In acute liver failure presentations, markedly subnormal serum ALP (typically < 40 IU/L) is characteristic of Wilson disease and represents a life-threatening emergency requiring urgent transplant evaluation. 1, 6

Diagnostic Features

• Accompanied by Coombs-negative hemolytic anemia, vitamin K-resistant coagulopathy, and modest aminotransferase elevations (typically < 2000 IU/L) 1
• An ALP-to-total bilirubin ratio < 2 is highly specific for Wilson disease in acute liver failure and should trigger immediate evaluation for liver transplantation 1
• Serum copper concentrations are usually ≥ 200 µg/dL (≈ 31.5 µmol/L), and 24-hour urinary copper excretion is markedly elevated 1
• Kayser-Fleischer rings may be absent in approximately 50% of patients presenting with acute liver failure 1
• The low ALP reflects massive hepatocyte necrosis with copper-mediated inhibition of ALP activity 1

Critical Pitfall

Failure to recognize Wilson disease in young adults (< 40 years) with acute liver failure and an ALP-to-bilirubin ratio < 2 can delay life-saving liver transplantation. 1

Secondary Causes of Low ALP

Nutritional and Metabolic

• Malnutrition and micronutrient deficiencies (zinc, magnesium, vitamin C) can lower ALP 2
• Vitamin D deficiency may be associated with low ALP, though this typically causes elevated ALP in osteomalacia; the relationship is complex 2
• Hypothyroidism and other endocrine disorders can suppress ALP 2

Medication-Induced

• Antiresorptive medications (bisphosphonates, denosumab) lower ALP levels by reducing bone turnover 1, 2
• These medications can cause PLP levels to appear relatively elevated due to reduced enzymatic degradation 1
• A comprehensive medication review is essential, particularly in older patients 1

Chronic Liver Disease

• In patients with chronic liver disease, low serum ALP (< 40 IU/L) occurs in approximately 0.25% and is associated with significantly lower serum aminotransferase and bilirubin levels throughout follow-up 7
• Patients with consistently low ALP levels show less biochemical evidence of active liver disease compared to those with normal or elevated ALP 7

Hematologic

• Severe anemia and blood transfusions can transiently lower ALP 2
• Pernicious anemia (vitamin B12 deficiency) may be associated with low ALP 2

Diagnostic Algorithm

Step 1: Confirm Persistence

• Repeat ALP measurement to confirm that the low level is persistent rather than transient 2, 4
• Persistently low ALP is defined as low levels on the majority of measurements over time 4

Step 2: Exclude Wilson Disease (If Acute Presentation)

• In any patient < 40 years with acute liver failure and low ALP, immediately calculate the ALP-to-bilirubin ratio 1
• If ratio < 2, urgently measure serum copper, 24-hour urinary copper, and ceruloplasmin, and perform slit-lamp examination for Kayser-Fleischer rings 1
• Expedite hepatology and transplant surgery consultation 1

Step 3: Measure ALP Substrates

• Pyridoxal-5'-phosphate (PLP, vitamin B6): Elevated levels strongly suggest hypophosphatasia; all individuals with PLP above the reference range in one study carried an ALPL mutation 3
• Urinary phosphoethanolamine (PEA): Elevated levels support enzyme deficiency 2, 3
• Bone-specific ALP: May be low even when total ALP is normal, particularly useful when hypophosphatasia is suspected 5

Step 4: Clinical Assessment

• Dental history: Premature loss of primary teeth before age 5 years is highly suggestive of hypophosphatasia 1
• Musculoskeletal symptoms: Skeletal pain, stress fractures, pseudofractures, chondrocalcinosis, calcific periarthritis 1, 2
• Medication review: Identify antiresorptive therapy (bisphosphonates, denosumab) 1, 2
• Nutritional assessment: Screen for malnutrition, zinc deficiency, magnesium deficiency 2

Step 5: Genetic Testing

• When clinical and biochemical findings suggest hypophosphatasia (elevated PLP, elevated PEA, low bone-specific ALP), perform whole-gene sequencing of ALPL to confirm pathogenic variants 1, 2
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation 3
• Six novel mutations were identified in one cohort, indicating ongoing discovery of pathogenic variants 3
• Most mutations are heterozygous and missense, with the majority predicted to have a damaging effect on protein activity 3

Step 6: Consider Other Secondary Causes

• Laboratory evaluation: Complete blood count (anemia), thyroid function tests (hypothyroidism), serum zinc and magnesium, vitamin D level 2
• Liver function tests: If chronic liver disease is suspected, assess aminotransferases, bilirubin, albumin, and INR 7

Clinical Significance and Management Implications

Hypophosphatasia and Osteoporosis

• Hypophosphatasia may be misdiagnosed as osteoporosis, leading to inappropriate treatment with antiresorptive therapy, which is relatively contraindicated in hypophosphatasia 4
• Persistently low ALP in osteoporosis clinic attendees (< 30 IU/L) signals the possibility of hypophosphatasia and should prompt further evaluation before initiating antiresorptive therapy 4
• In one study, 9% of osteoporosis clinic patients had at least one low ALP measurement, and 0.4% had persistently low ALP 4

Atypical Femoral Fractures

• Low ALP was found in 2 out of 22 patients (9%) with atypical femoral fractures, suggesting a possible association with hypophosphatasia 4

Prevalence in Different Settings

• Osteoporosis clinic: 9% have ≥ 1 low ALP; 0.4% have persistently low ALP 4
• Hospital-wide: 0.6% of all hospital patients have low ALP 4
• Chronic liver disease clinic: 0.25% have consistently low ALP 7

Key Pitfalls to Avoid

1. Do not dismiss low ALP as benign or a laboratory artifact without confirming persistence and excluding secondary causes 1

2. Do not overlook Wilson disease in young adults with acute liver failure and low ALP; calculate the ALP-to-bilirubin ratio immediately 1

3. Do not initiate antiresorptive therapy in patients with persistently low ALP without first excluding hypophosphatasia 4

4. Do not rely solely on total ALP; measure bone-specific ALP when hypophosphatasia is suspected, as total ALP may be normal while bone-specific ALP is low 5

5. Do not assume that a negative ALPL exon sequencing result excludes hypophosphatasia; patients may carry unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes 2